The chemoattractant properties of chemokines are well established. However, chemokines also have important non-immune functions including neuronal excitation. Both chemokines and gp120 produce mechanical allodynia when injected intradermally (i.d.) in the rat. In vitro studies suggest that it results from the ability of chemokines and gp120 to directly excite or sensitize primary afferent neurons. The overall goal of this proposal is to further test the hypothesis - in vivo - that chemokines produce allodynia and hyperalgesia by a peripheral action that involves either direct or indirect excitation or sensitization of primary afferent neurons. These studies will focus on SDF-1 and gp120, two structurally distinct ligands for the CXCR4 receptor. The specific aims of this proposal are to (1) characterize the relative potency and efficacy, behavioral modalities affected, and temporal nature of the effects produced by i.d. injection of SDF-1 and of gp120 in the rat; (2) determine which populations of immunohistochemically identified primary afferent neurons express CXCR4 receptors in vivo, and (3) determine which classes of physiologically-identified primary afferent neurons are excited or sensitized by i.d. injection of SDF-1 or gp120. These highly integrative and complementary studies will provide new information about a previously unappreciated role of chemokines as peripheral mediators of nociception and the mechanisms responsible. Through their focus on the CXCR4 receptor, these results may also shed new insight into the mechanisms of sensory neuropathy and pain associated with HIV.